Efficient stereoselective synthesis of aryl lactones using engineered ketoreductase <i>Ch</i>KRED20 from <i>Chryseobacterium</i> sp. CA49

Shi, Mingliang; Lin, Rude; Yu, Yuan; Yao, Yao; Fan, Xinyue; Li, Kun; Wu, Zhongliu; Yu, Xiaoqi; Liu, Yan; Wang, Na

doi:10.1039/d3qo02076b

Cited by 3 publications

(2 citation statements)

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“…Lactones are cyclic carboxylic esters . Lactones with five (γ)- or six (δ)-membered rings are characteristic components of fruity and milky fragrance and have wide applications in the food and fragrance industry. , Furthermore, some polycyclic lactones are well-known pharmaceutics that presently act as biologically active compounds for various medical problems, which are used in different kinds of pharmaceutical industries. , Some examples of these are bicyclic and polycyclic γ-lactones applied in many salutary physiological functions, such as antitumor, anticancer, anti-inflammatory, and immunosuppressant. , They are synthesized chemically due to their bare appearance in nature. , However, chemical synthesis of lactones via Baeyer–Villiger (BV) oxidation involves many disadvantages, including harsh conditions, chemical pollution, and low selectivity. , Therefore, the enzymatic synthesis of lactones has become more attractive in recent years. Baeyer–Villiger monooxygenases (BVMOs) can catalyze oxygenation of a variety of cyclic and aliphatic ketones into lactones and esters, respectively .…”

Section: Introductionmentioning

confidence: 99%

“…4,5 Some examples of these are bicyclic and polycyclic γ-lactones applied in many salutary physiological functions, such as antitumor, anticancer, anti-inflammatory, and immunosuppressant. 6,7 They are synthesized chemically due to their bare appearance in nature. 8,9 However, chemical synthesis of lactones via Baeyer− Villiger (BV) oxidation involves many disadvantages, including harsh conditions, chemical pollution, and low selectivity.…”

Section: Introductionmentioning

confidence: 99%

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Simultaneously Enhanced Catalytic Activity and Thermostability of a Baeyer–Villiger Monooxygenase from Oceanicola granulosus by Reshaping the Binding Pocket

Du,

Lv,

Feng

et al. 2024

J. Agric. Food Chem.

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Enzymatic oxygenation of various cyclic ketones into lactones via Baeyer−Villiger monooxygenases (BVMOs) could provide a promising route for synthesizing fragrances and pharmaceutical ingredients. However, unsatisfactory catalytic activity and thermostability restricted their applications in the pharmaceutical and food industries. In this study, we successfully improved the catalytic activity and thermostability of a Baeyer−Villiger monooxygenase (OgBVMO) from Oceanicola granulosus by reshaping the binding pocket. As a result, mutant OgBVMO-Re displayed a 1.0-to 6.4-fold increase in the activity toward branched cyclic ketones tested, accompanied by a 3 °C higher melting point, and a 2-fold longer half-life time (t 1/2 (45 °C)). Molecular dynamics simulations revealed that reshaping the binding pocket achieved strengthened motion correlation between amino acid residues, appropriate size of the substrate-binding pocket, beneficial surface characteristics, lower energy barriers, and shorter nucleophilic distance. This study well demonstrated the trade-off between the enzyme activity and thermostability by reshaping the substrate-binding pocket, paving the way for further engineering other enzymes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Simultaneously Enhanced Catalytic Activity and Thermostability of a Baeyer–Villiger Monooxygenase from Oceanicola granulosus by Reshaping the Binding Pocket

Du,

Lv,

Feng

et al. 2024

J. Agric. Food Chem.

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Reversing the Enantioselectivity of Enzymatic Dynamic Kinetic Asymmetric Transformations in the Synthesis of Fused Lactones

Shi,

Yao,

Fan

et al. 2024

ACS Catal.

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The rational design of one ketoreductase into stereocomplementary variants for controlling the stereoselectivity of bulky chiral molecules bearing contiguous stereocenters is highly desirable and challenging. Herein, we report protein engineering of ketoreductase from Chryseobacterium sp. CA49 (ChKRED20) through targeted mutagenesis of only two key residues (Y188 and H145) located in the enzyme pocket, achieving the precise stereocontrol over the synthesis of tricyclic fused lactones (highest reversing enantioselectivity from >99:1 e.r. to <1:99 e.r.). Notably, both kinetic resolution asymmetric reduction (KR-AR) and dynamic kinetic asymmetric transformation (DyKAT) were observed in this system. In the KR-AR process, ChKRED20 variants exclusively convert (R)-or (S)-keto esters to corresponding enantio-and diastereoenriched (R,S)-or (S,R)-cis-lactones and deliver leftover (S)-or (R)-keto esters. On the contrary, in the DyKAT process, unreactive configurations of substrates undergo efficient equilibration via an enolization through protonation− deprotonation in enzymes. Computational studies are also conducted to get insight into the origin of stereoselectivity and enantioselectivity.

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Efficient Chemoenzymatic Cascade Reaction for One-Pot Enantioselective Synthesis of Chiral Indole Derivatives in Water

Zhao,

Li,

Yao

et al. 2024

Preprint

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Efficient stereoselective synthesis of aryl lactones using engineered ketoreductase ChKRED20 from Chryseobacterium sp. CA49

Abstract: Enzymatic asymmetric reduction of γ, δ-keto esters offer a convenient and efficient approach for producing optically active lactones. However, aryl lactones with bulky structures may not be readily prepared using...

Cited by 3 publications

References 48 publications

Simultaneously Enhanced Catalytic Activity and Thermostability of a Baeyer–Villiger Monooxygenase from Oceanicola granulosus by Reshaping the Binding Pocket

Simultaneously Enhanced Catalytic Activity and Thermostability of a Baeyer–Villiger Monooxygenase from Oceanicola granulosus by Reshaping the Binding Pocket

Reversing the Enantioselectivity of Enzymatic Dynamic Kinetic Asymmetric Transformations in the Synthesis of Fused Lactones

Efficient Chemoenzymatic Cascade Reaction for One-Pot Enantioselective Synthesis of Chiral Indole Derivatives in Water

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